Correspondence/Rebuttal Cite This: Environ. Sci. Technol. 2018, 52, 13657−13659
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Comment on “TBBPA and Its Alternatives Disturb the Early Stages of Neural Development by Interfering with the NOTCH and WNT Pathways”
Environ. Sci. Technol. 2018.52:13657-13659. Downloaded from pubs.acs.org by 93.179.91.178 on 11/26/18. For personal use only.
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battery. Based upon the fact that TBBPA is rapidly metabolized, it is not clear whether Nakajima et al.3 actually measured the parent compound or inactive metabolites but of greater concern is the dosage claimed where it is wellestablished by the NTP6 and Sanders et al.7 of the NIH that TBBPA doses required to produce an effect exceed 200 mg/kg. The use of Nakajima et al.3 as a citation for brain TBBPA brain accumulation and a neurobehavioral effect is questionable in light of previously published papers. Yin et al.2 (2018) neglected to cite the preponderance of findings indicating that TBBPA does not reach the brain following oral in vivo administration.8 Although Yin et al.2 suggest that embryonic stem cells serve as a model for neural developmental toxicity, it is well-established through in vivo studies that TBBPA does not reach the brain; and hence, biological relevance of effects of this chemical in vitro, especially as an inference for behavioral alterations, remain questionable. Cope et al.9 examined reproductive, developmental and neurobehavioral effects following oral exposure of TBBPA on Sprague−Dawley rats, which is especially important in light of in vitro study of Yin et al.2 Cope et al.9 found in vivo conditions that doses as high as 1g/kg/day, not biologically relevant, over the course of two generations produced no significant effects on reproduction, growth or development. There was no evidence of developmental neurotoxicity or neuropathology. These observations were confirmed by Williams and DeSesso10 who also demonstrated under in vivo conditions that TBBPA produced no adverse effects on neurodevelopment, neuromotor functions, learning, memory and other neurobehavioral end points at doses up to 1g/kg/ day. Further, histopathological examination of the brain revealed no alterations. It is thus evident that a relatively high dose of TBPPA did not, under in vivo conditions, produce any adverse effects on neuronal behavior and function and no evidence of pathological alterations. The biological relevance of in vitro data in the embryonic stem cells remains questionable in light of absence of any findings in vivo at high TBBPA concentrations. Yin et al. argue that “Animal tests already showed that TBBPA impaired neural development”, citing two studies in zebrafish.11 However, Fraser et al.12 showed that behavioral studies with zebrafish were conducted with bisphenol (BPA) and results were dependent upon lighting conditions. These findings do not apply to mammalian conditions and are not evidence of an adverse neurobehavioral effect attributed to TBBPA. In the Chen et al. study,13 zebrafish larvae exposed to 5 uM TBBPA from 8 to 48 h demonstrated lower average activity and speed of movement, but this effect diminished from 48 to 96 h. TBBPA also produced morphological malformations and mortality. In
s board-certified toxicologists, our main concerns include that this article: (1) fails to recognize and acknowledge scientifically published in vivo data that may be more relevant for risk assessment, especially for human exposure and neurodevelopment; (2) utilizes an embryonic stem cell system that is not representative of neurobehavioral and/or neuronal function, and which lacks the essential components of the functions of a blood-brain barrier which plays a key role in chemical entry into the brain and neurodevelopment; and (3) makes generalizations regarding brominated flame retardants that do not always comport with the science. One of the aims of this investigation was to “evaluate the cytotoxicity and neural development toxicity of TBBPA, TBBPS, and TCBPA with a mouse embryonic stem cell system” as “high detection rates in human breast milk and umbilical cord serum have raised concerns about the adverse effects on human fetal development”. In order to make accurate decisions regarding exposure and potential adverse effects, regulatory agencies benefit from in vivo data from humans where feasible and available, as well as data from animal in vivo studies. The goal of using in vitro data is often to determine a mode or mechanism of action, but this practice has limitations, since the processes of absorption, distribution, metabolism and excretion (ADME) are lacking with respect to human exposure studies. Human exposure in real life settings is especially important for neuronal function where a blood-brain barrier may limit or prevent entry of the chemical into the brain. This is the case for TBBPA, where administration to humans intravenously at 0.1 mg/kg or rats at 300 mg/kg orally resulted in an inactivated glucuronide within 3 h that was slowly eliminated in urine.1 The overwhelming scientific evidence indicates that the active parent TBBPA was rapidly conjugated to an inactive form of TBBPA and eliminated, demonstrating that this chemical does not accumulate, particularly in brain regions, as it does not reach the brain and does not cross the blood-brain barrier. Yin et al.2 citation to Nakajima et al.3 findings that TBBPA accumulates in brain regions, including the striatum, in mice and is associated with behavioral alterations is questionable in light of the overwhelming evidence to the contrary. It is worthwhile noting that within 3 h following administration of 300 mg/kg TBBPA to rats, this compound was metabolized to a glucuronide or a sulfate indicating the absence of parent TBBPA accumulation.4 In the Nakajima et al.3 study, treatment with TBBPA at 0.1 or 5 mg/kg produced an apparent accumulation of chemical in the striatum after 3 h, but it is not clear whether these authors measured parent or inactive metabolite. Second, data are overwhelming that doses as high as 1000 mg/kg TBBPA produced no neurobehavioral effects in rats,5 which is in contrast to minor changes in neurobehavioral parameters reported with minimal doses (0.1 or 5 mg/kg) where there was a lack of a positive control to assess performance of the test © 2018 American Chemical Society
Published: October 30, 2018 13657
DOI: 10.1021/acs.est.8b05091 Environ. Sci. Technol. 2018, 52, 13657−13659
Environmental Science & Technology
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contrast, in vivo TBBPA at 1g/kg/day for 2 years produced no pathological alterations and no mortality. Currently, the biological relevance of a temporary change in zebrafish behavior which disappears with duration is not clear, and it is not evidence that TBBPA produces impaired neural development in animals, particularly given that other manifestations seen in zebrafish as mortality and morphological alterations did not occur in mammals. The findings in these two zebrafish studies argue against the use of data from Fraser et al.12 and Chen et al.13 to support extrapolation to humans and neuronal effects in rats, especially since the observations “are dependent on minor methodological alterations”.12 Yin et al.2 also cite Kim et al.14that suggested that TBBPA induced the central nervous system and that TBBPA accumulated in body fluids. These results are contrary to the preponderance of published findings demonstrating that TBBPA does not bioaccumulate. In addition, Kim et al.14 utilized high doses of TBBPA to determine whether this chemical affected hippocampal neurogenesis. Oral TBBPA is rapidly inactivated in humans and eliminated and thus does not reach the brain4 which was confirmed in rats where TBBPA was rapidly eliminated and did not reach the brain.1 It should also be noted that Kim et al.14 used male C5BL/6 mice to show that TBBPA at high doses reduced hippocampal neurogenesis and adversely affected memory retention. Since TBBPA did not alter neural functions, behavior and histopathology in rats, it would seem that the mice used in Kim et al.14 may be uniquely different, and that effects noted may be species-specific. The findings in mice raise the question of biological relevance for risk assessment, especially for humans, and provide support for the hypothesis that environmentally relevant amounts of TBBPA are not neurotoxic. Yin et al.2 (2018) state that “TBBPA was found to accumulate in the brain”, which was not supported by data from humans and rats.1 The National Toxicology Program6 found no effects of TBBPA on brain functions and no evidence of neuropathologic alterations. The authors cite Lilienthal et al.15 stating that TBBPA produced neurobehavioral effects in offspring based on an auditory stimulus test (AST). However, the standard accepted by most regulatory agencies is a Functional Observatory Battery (FOB) test, which demonstrated no adverse effects. The relevance of the AST observations in this context is questionable, has not been repeated, and dose levels used in these studies greatly exceeded concentrations detected in the environment. Yin et al.2 appear to have failed to consider relevant data in the scientific literature, including the fact that dose levels in Lilienthal et al.15 exceeded concentrations detected in the environment. Using lab animal and in vitro studies to predict potential human health risk can have limitations. While such studies may be useful, this type of information is not directly representative of human health risk.
Correspondence/Rebuttal
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the North American Flame Retardant Alliance (NAFRA) of the American Chemistry Council, which has provided funding and honoraria to the authors as members of NAFRA’s Science Advisory Council. The researchers’ scientific conclusions and professional judgments were not subject to the funder’s control.
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REFERENCES
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Sam Kacew*,†,‡ A. Wallace Hayes‡ †
Mclaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario Canada ‡ University of South Florida College of Public Health and Institute for Integrative Toxicology, Michigan State University, Tampa, Florida United States 13658
DOI: 10.1021/acs.est.8b05091 Environ. Sci. Technol. 2018, 52, 13657−13659
Environmental Science & Technology
Correspondence/Rebuttal
(10) Williams, A. L.; DeSesso, J. M. The potential of selected brominated flame retardants to affect neurological development. J. Toxicol. Environ. Health, Part B 2010, 13, 411−448. (11) Chen, J.; Tanguay, R. L.; Xiao, Y.; Haggard, D. E.; Ge, X.; Jia, Y.; Zheng, Y.; Dong, Q.; Huang, C.; Lin, K. TBBPA exposure during a sensitive window produces neurobehavioral changes larval zebrafish. Environ. Pollut. 2016, 216, 53−63. (12) Fraser, T. W. K.; Kherzi, A.; Jusdado, J.G. H.; LewandowskaSabat, A. M.; Henry, T.; Ropstad, E. Toxicant induced behavioral aberrations in larval zebrafish are dependent on minor methodological alterations. Toxicol. Lett. 2017, 276, 62−68. (13) Chen, J.; Tanguay, R. L.; Xiao, Y.; Haggard, D. E.; Ge, X.; Jia, Y.; Zheng, Y.; Dong, Q.; Huang, C.; Lin, K. TBBPA exposure during a sensitive window produces neurobehavioral changes larval zebrafish. Environ. Pollut. 2016, 216, 53−63. (14) Kim, A. H.; Chun, H. J.; Lee, S.; Kim, H. S.; Lee, J. High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention. Food Chem. Toxicol. 2017, 106, 223−231. (15) Lilienthal, H.; Verwer, C. M.; van der Ven, L. T.; Piersma, A. H.; Vos, J. G. Exposure to tetrabromobisphenol A (TBBPA) in Wistar rats: Neurobehavioral effects in offspring from a one-generation reproduction study. Toxicology 2008, 246, 45−54.
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DOI: 10.1021/acs.est.8b05091 Environ. Sci. Technol. 2018, 52, 13657−13659
